Ovarian Cancer—New Thinking on Old Regimens
2011 Feb 23, Nelson Teng
Nelson Teng, MD, PhD, is Director of Gynecologic Oncology and Associate Professor of Obstetrics and Gynecology at Stanford University School of Medicine. Dr. Teng is also Program Director for the Stanford/UCSF Gynecologic Oncology Fellowship Program in Stanford, California. For more information, view his profile.

The basis for using intraperitoneal chemotherapy comes from several randomized studies including the now old Gynecologic Oncology Group (GOG) study by Armstrong et al, published in the New England Journal of Medicine in 2006; however, there is a renewed interest in this topic, which has now become an important subject.1

In spite of all of the advances that biologics and newer drugs, the so-called triplet combinations, have made beyond the old standard doublet of carboplatin and paclitaxel as first line therapy, for the most part, either the result is not entirely confirmatory with survival data yet or the drug has shown minimal effect in other solid tumors. Case in point is the findings from the ICON7 trial2 and OCEANS trial which are very encouraging, but we don’t have the final results. It is not clear whether any of the studies of these new regimens will have the same kind of impact on survival of those that I would consider the most important studies published in ovarian cancer in the past decade.

One of those studies is the one I mentioned, which looked at intraperitoneal therapy, and the other one was published by the Japanese Gynecologic Oncology Group (GOG), and looked at dose-dense (not dose intense, e.g. with marrow transplant or stem cell support) chemotherapy in advanced ovarian cancer.3 We can compare these two studies.

In the first study, which is well-known, intraperitoneal vs intravenous cisplatin and paclitaxel were compared. Intraperitoneal therapy showed a tremendously impressive extension of not only the progression-free interval, but also overall survival. The median progression-free survival was increased from 18.3 months to 23.8 months (P = .05) and the median survival difference was 49 months vs 65 months (P = .03), a difference of almost 14 months, which is a whopper in any kind of drug study.

Had this study been not on just a procedure, a technique of intraperitoneal devices, but on a drug of some kind, showing this degree of improvement in survival, it would have been an instantaneous hit and the drug probably would be used even without waiting for completion of an additional confirmatory study. There have been at least three randomized trials that have demonstrated superiority of intraperitoneal over intravenous delivery of platinum-based chemotherapy in patients with optimally debulked advanced ovarian cancer, but intraperitoneal therapy hasn’t really caught on.

There has always been a question in my mind as to why this should be the case. Then, about a year ago, the Japanese GOG reported results from what I consider to be a very well-designed phase III trial showing the benefit of dose-dense, once weekly paclitaxel. When compared with the patients assigned to the conventional regimen of paclitaxel and carboplatin, those on the dose-dense paclitaxel plus carboplatin regimen showed improvement of both the progression-free interval and overall survival. Progression-free survival was 28.0 months and 17.2 months, respectively (hazard ratio [HR] 0.71; 95% CI 0.58–0.88; P = 0.0015). The 3-year overall survival rate was 72.1% vs 65.1% (HR, 0.75; CI, 0.57–0.98; P = 0.03).

A very interesting correlation can be made concerning the possible mechanism of intraperitoneal therapy and also the weekly dosing investigated by the Japanese study. If we consider the reasons that intraperitoneal therapy works, it becomes obvious that it is not simply just the fact that the drug is delivered directly into the abdominal cavity, where most of the ovarian cancers reside. The major mechanism may, perhaps, be a depot, slow release effect by which the intraperitoneal drug, paclitaxel or cisplatin, actually circulates into the blood systemically over time. We know that paclitaxel, when given intraperitoneally, has a very, very long half-life, hence a “dose-dense” effect.

The dosing in the Armstrong study is actually similar to the dose-dense chemotherapy in the Japanese study that was given weekly. Armstrong and colleagues gave 80 mg of paclitaxel per week for 3 weeks. Carboplatin was given at the standard dose, AUC of 6. If we add up the three treatments of paclitaxel, the total dose was 240 mg, which is higher than what we typically use as a pulsed dose of 175 mg. So, by distributing the dose over time, we may have achieved a similar mechanistic effect to that of the intraperitoneal depot effect.

Of course, one of the issues here is that hematologic toxicity is frequently dose-limiting. Hematologic toxicity, particularly thrombocytopenia, is carboplatin-related. Somehow, with intraperitoneal delivery or dose-dense therapy, we can actually reduce the incidence of this toxicity.

Another issue is higher hematologic toxicity with intravenous chemotherapy than with intraperitoneal chemotherapy. The real question is whether we are able to use these two studies to advance the field by looking at a different regimen, as well as a more convenient way of administering therapy instead of intraperitoneally, by actually using intravenous therapy.

Currently, GOG is conducting a trial, GOG 252, in which they compare the different intraperitoneal dose-dense regimens and, then, just to do the fashionable thing, will add bevacizumab to all of the regimens, which will be followed by bevacizumab maintenance therapy. It does not directly compare intraperitoneal and intravenous delivery; nevertheless, we may get a useful result. In short, there is a significant contribution to be made by really looking at the therapy that we already have on hand. For example, in pediatric acute lymphoblastic leukemia, significant improvement in survival was achieved in the past several decades without the introduction of any new drugs.

There are several things to consider in these two studies. One common criticism of both studies is the high dropout rate. Of interest, both studies have very similar dropout rates. In fact, in the intraperitoneal study, only 42% of patients received all six cycles of chemotherapy and in the experimental arm of the Japanese study, 48% received all six cycles. However, if all the patients had completed the six-cycle treatment in either of these two studies, the result would have been even more dramatic. The high noncompletion rate was caused, mainly, by severe hematologic and neurologic toxicity, pain, and fatigue.

Another criticism is that the Japanese population might be different from others, so there may be ethnic or racial differences. For example, there is a difference in histologic distribution of tumors, with higher incidence of clear cell carcinoma in the Asian population; clear cell carcinoma carries a poorer prognosis. However, when the Japanese analyzed only the serous papillary tumors, they still observed an improvement in survival. In fact, in their study, using the dose-dense schedule did not show an obvious impact on outcomes in patients with clear cell carcinoma.

There are other differences in the inclusion criteria, such as the inclusion of stage II disease in the dose-dense trial, whereas, only stage III patients were studied in the intraperitoneal trial. There might also be variation in the surgical debulking techniques used. The GOG 252 trial probably will be one of the studies in which these questions can be answered.

There are other intriguing mechanisms involved. For example, paclitaxel, given at a low dose may have, in itself, an anti-angiogenesis effect, which may be synergistic with the chemotherapy regimen, especially when paclitaxel is given in a dose-dense manner. One wonders if this would explain why in the phase III GOG 218 trial, which looked at bevacizumab in women with advanced ovarian cancer, an improvement in progression-free survival was only observed in patients who received continued bevacizumab maintenance therapy. Women treated with carboplatin and paclitaxel, with or without bevacizumab, showed no difference in progression-free survival.4 The anti-angiogenesis effect may already be maximized by paclitaxel, such that the addition of bevacizumab to chemotherapy showed no significant improvement.

By better dosing, which could be a lower dose of both carboplatin and paclitaxel, the hematologic and other toxicities can be reduced. The kinetics may be more similar to that of the traditional low dose, continuous metronomic chemotherapy. Although the verdict is still out on whether these traditional therapies should be pushed aside in favor of biologics, consideration must be given to the side effects of the newer agents, especially longer term and also a serious issue relative to cost.

These two seemingly very different types of regimen may share a common mechanistic fundamental. The result of one study actually affirmed the other. There were two different methodologies, evaluated in very different patient populations, yet showing comparable superior survival curves. Further investigation of the old drugs with innovative dosing and scheduling, and also delivery, may be in order.

I just finished reading this article before logging in here. I also wanted IP chemo and my doc just wouldn't go for it. One point made in this article is that perhaps dense dose chemo has the same effect at IP chemo in delivering the drugs long term, ie they linger longer in your system. If there's a recurrence for me I'm going to push hard for the dense dose regimen.
I'll bet I'm not the only one who gets a little excited when there's a News story about ovarian cancer.

I am not in remission and only was once for several months since my initial dx 8/2006. My doctor is very pro IP treatments and I have had many (18). The first 6 were very toxic and I had a lot of pain until I realized that I could almost live on pain meds. He also reduced the saline fluid so that I did not have discomfort from that. The next 12 were pretty uneventful other than the fact that I had to be admitted for overnight because of potential complications with the IP port and insurance requirements. This disease for me is always lingering around but has never been in a major organ (so far). I cannot explain it in medical terms but he feels good about my results even though he was always shooting for NED and that just has not happened. He certainly feels that the IP was a very positive treatment for me but he does look at all of them collectively and not individually. I was told that he has a very high rate of women finishing the cycles of IP treatment where many times the cycle is maybe halfway completed. I am also surprised to read "it has not caught on" and thought that this was now a very standard procedure in the past couple of years. I don't know if this information is too meaningful for you guys but I just thought I would send you my experience about this subject and my doctors aggressive approach to IP treatments. J. :)

Has anyone looked at the "quality of life" (QOL) studies that have been done on intraperitoneal chemotherapy? Unfortunately, the outcome is not encouraging but at least someone is looking into this aspect of survival.

From the article posted: "The high noncompletion rate was caused, mainly, by severe hematologic and neurologic toxicity, pain, and fatigue." First, the authors are talking about lower toxicity with IP but then there are still problems with "severe hematologic & neurologic toxicity." What's up with that?

The QOL studies also looked at depression and found a high correlation between depression and IP treatment. But maybe that just goes with the chemo for OC in general.

I'd like to know if anyone else weeps/was weeping for several days after receiving chemo. I noticed that I had unprovoked weeping after the fourth dose of carboplatin which I found interesting to experience. Like hormonal, PMS-type, "black cloud" depression that lifts suddenly after a short period of time. I read that there is a 35% increase in urinary excretion of serotonin (the neurotransmitter that is often low in depression) after using carboplatin. The anti-nausea meds given with chemo also lower serotonin.

In my opinion, one of the significant differences between us and the Japanese (who live in Japan) is the daily iodine intake. The Japanese daily iodine intake is approximately 12 mg/day. In the US, the average daily iodine intake is less than 1 mg (even less if a person is on a low-salt diet). The Japanese (living in Japan) enjoy the lowest worldwide incidence of breast and prostate cancer (that vanishes when Japanese people live in the US and adopt the Western diet). In the US, the fluoride in the drinking water interferes with iodine utilization. And so do the bromides in the food supply from bread and pesticides (but I should probably post that on another discussion board).

I had IP treatment after my illeostomy was reversed as part of my frontline treatment. I had 5 IV carbo/taxol, illeostomy reversal then 3 rounds of IP cisplat/ IV taxol. I would definately agree that my QOL was impaired with the IP treatment. I also have to consider that my 'big' surgery was very involved. Not only did I have an illeosomy but I also had a chest tube and was very weakend. After my illeostomy reversal I started the IP treatment as soon as I was able. So I was newly post-op. Of course prior to getting ill I was in great physical shape and never sick! So I went into my surgery with a young, physically fit body. I also had crying jags after treatment. I do remember thinking "I don't know how long I can do this'. I also remember fearing a recurrence and thinking I can understand why people choose not to fight anymore. I was terrified I'd get to that point.

That, of course, was back in early 2009. Now looking back at it I can say 'it wasn't that bad' but it probably was that bad. That being said, if I had the opportunity to do IP again I would.

I tend to blame it on the chemo. It was always a day or two after chemo, like clock work. Several days later I'd feel so much better. I was also very fatigued by the IP chemo. I'm usually a busy person. I think not being able to do the things I wanted/needed to left me feeling depressed. Also, my kids were 3 and 5 at the time. I never really had time to baby myself. I remember I'd drag myself out of bed to get them dressed for school and make their lunches. I had my older daughter living with me at the time but this was something I wanted to do. After they left for school I'd lay in their room and just cry.

I am experiencing extreme fatigue lately. I attribute it to my elevated ALT&AST levels as well as the chemo. It is really setting back physically and emotionally. My ALT, AST and ALP have all dropped so I am scheduled to have my 3rd infusion of Taxol tomorrow. VERY pleased about that.

I don't think I had many symptoms from my surgical menopause. Not hot flashes at all and it is 2 1/2 years since my surgery.

I think the reason I think I feel so good on every other chemo BUT taxol is that horrible "taxol-fatigue" is gone. I still LOVE taxol because it got me to the 2 brief remissions I had, but I do associate it with serious fatigue.

I'm so glad, Nancy, that you ALT levels, etc. all dropped! Glad you can get more of that magic cancer-killing taxol in you tomorrow! I have faith in your taxol/avastin combo you're getting and would LOVE to be able to get that myself. (but taxol stopped working for me after 23 infusions of it. boo.)

I tolerated Taxol very well - not a lot of fatigue and virtually no neuropathy - and I had a total of 18 infusions. It's some good bug juice, for sure! I credit the Taxol with giving me a year of good health, following my first line treatment.

I have no idea when I went thru menopause, whether it was pre-surgery or post-surgery. I had my uterus and cervix removed years ago, at age 33, and waited and waited and waited for symptoms of menopause. They never came. No hot flashes. Nothing. It was a non-event for me. I have known tons of women, however, including my mom, who suffered from severe hot flashes and depression, mood swings, etc with menopause. My mom's lasted 5 years. She experienced a very gradual menopause, instead of the sudden onset that some women have. I was going thru adolescence at the same time she was going thru menopause. Needless to say, our relationship was a mess. We were either swimming in the estrogen ocean, or suffering a draught.

I was hyper-emotional for a couple of months after my diagnosis and surgery. Not sure if it was the chemo or the sensory overload that comes with that kind of news....you have late stage ovarian cancer. I cried a LOT. At everything. My granddaughter said to me, "Nana, I'm going to stop coming to church with you because you always cry, and then I start crying, and I can tell by the way people look at us, they think we're crazy." It was true....some of the hymns made me cry.

You are 100% right....the ovaries are where the estrogen and other hormones come from. What I meant, probably very poorly said, was that after I had my uterus/cervix removed, I no longer had periods, and thus missed the early signs of menopause onset (light periods, skipped periods, etc). Without the indicator of menstrual flow, or lack thereof, it's difficult to tell when one enters menopause. So that's why I said I had no idea when menopause set in for me, since I wasn't having periods, and I had no other symptoms (hot flashes, etc).

I also had IP chemo alomg with Taxol and Carbo IV. 6 IP infusions and 12 IV infusions later I am NED. I did however have the crying spells. I cried over everything!! seems like I was always on the edge of crying and something would show up to push me over the edge. It could have been a halmark commercial and I was a blubbering mess. During the IP infusions, I also had such severv abdominal pain that I also lived on pain meds. It's been 7 months since my last chemo and I still have neuropathy in my feet and legs. I started cheno just a few weeks after a major debulking that included a bowel resection in 2 places and I also developed a blood clot in my messenteric vein. So, with all that I now also have digestion issues. BUT if given the chance to do it again, i WOULD definately do the IP again. if I have a recurrance I will push for IP again as well. It is a trade off i guess. I will live with the neuropathy and digestive issues so I can stay NED. I can live with that. :) Ip is a tough treatment but well worth it. I don't think I would have had such a good outcome with just the IV chemo. OK, long winded I know. :) Still praying for everyone on this board!! ((((HUGS))))

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